US4229575A - 7-(2,3-Dihydrobenzo-5-furanyl)-acetamido cephalosporin derivatives - Google Patents

7-(2,3-Dihydrobenzo-5-furanyl)-acetamido cephalosporin derivatives Download PDF

Info

Publication number
US4229575A
US4229575A US05/881,611 US88161178A US4229575A US 4229575 A US4229575 A US 4229575A US 88161178 A US88161178 A US 88161178A US 4229575 A US4229575 A US 4229575A
Authority
US
United States
Prior art keywords
amino
methyl
dihydro
benzofuranyl
oxo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US05/881,611
Other languages
English (en)
Inventor
Ekkehard H. Bohme
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Richardson Vicks Inc
Original Assignee
Richardson Merrell Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Richardson Merrell Inc filed Critical Richardson Merrell Inc
Priority to US05/881,611 priority Critical patent/US4229575A/en
Priority to ZA79254A priority patent/ZA79254B/xx
Priority to AU43701/79A priority patent/AU516917B2/en
Priority to IE790141A priority patent/IE790141L/xx
Priority to IL56574A priority patent/IL56574A0/xx
Priority to DE19792903909 priority patent/DE2903909A1/de
Priority to FR7904285A priority patent/FR2418234A1/fr
Priority to GB7906143A priority patent/GB2014996B/en
Priority to NL7901484A priority patent/NL7901484A/xx
Priority to BE193693A priority patent/BE874450A/fr
Priority to JP2090079A priority patent/JPS54122290A/ja
Priority to FR7918366A priority patent/FR2428636A1/fr
Application granted granted Critical
Publication of US4229575A publication Critical patent/US4229575A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • This invention is directed to new cephalosporin derivatives which are useful as antibiotics and methods of preparing same.
  • Compounds of the formula 1 are useful as antibiotics ##STR1## wherein W is H, --NHR 4 , --OH, --CO 2 R 5 or --SO 3 R 5 wherein R 4 is hydrogen, a straight or branched 2 to 5 carbon alkanoyl group or an alkoxycarbonyl group in which the alkoxy moiety is straight or branched and has from 1 to 4 carbon atoms.
  • R 5 is hydrogen or a straight or branched alkyl group of from 1 to 4 carbon atoms.
  • R 1 is hydrogen or methoxy.
  • R 2 is hydrogen, an alkanoyloxy group in which the alkanoyl moiety is straight or branched and has from 2 to 5 carbon atoms, or a heterocyclic thio group selected from 1,3,4-thiadiazol-2-ylthio, 5-methyl-1,3,4-thiadiazol-2-ylthio, 1,3,4-oxadiazol-2-ylthio, 5-methyl-1,3,4-oxadiazol-2-ylthio, tetrazol-5-ylthio, 1-methyltetrazol-5-ylthio, 1,2,3-triazol-5-ylthio and 1-methyl-1,2,3-triazol-5-ylthio.
  • R 3 is hydrogen, a straight or branched alkyl group of from 1 to 4 carbon atoms, an alkanoyloxymethyl group in which the alkanoyl moiety is straight or branched and has from 2 to 5 carbon atoms, an alkanoylaminomethyl group wherein the alkanoyl moiety is straight or branched and has from 2 to 5 carbon atoms and the amino nitrogen may be substituted with a straight or branched alkyl group of from 1 to 4 carbon atoms, an alkoxycarbonylaminomethyl group wherein the alkoxy moiety is straight or branched and has from 1 to 4 carbon atoms and the amino nitrogen may be substituted with a straight or branched alkyl group of from 1 to 4 carbom atoms, a p-(alkanoyloxy)benzyl group in which the alkanoyl moiety has from 2 to 5 carbon atoms and is straight or branched, or an aminoalkanoyloxymethyl group wherein the al
  • R 3 is hydrogen or a straight or branched alkyl group of from 1 to 4 carbon atoms.
  • R 3 may be an alkanoyloxymethyl group represented by the formula ##STR2## wherein R 7 is a straight or branched alkyl group of from 1 4 4 carbon atoms.
  • R 3 may be an alkanoylaminomethyl group or alkoxycarbonylaminomethyl group represented by ##STR3## wherein R 8 is a straight or branched alkyl group of from 1 to 4 carbon atoms or a straight or branched alkoxy group of from 1 to 4 carbon atoms and R 9 is hydrogen or a straight or branched alkyl group of from 1 to 4 carbon atoms.
  • R 3 may also be an alkanoyloxybenzyl group represented by the formula ##STR4## wherein R 10 is a straight or branched alkyl group of from 1 to 4 carbon atoms.
  • R 3 may also be an aminoalkanoyloxymethyl group represented by the formula ##STR5## wherein n is 0 to 5, and each of R 11 and R 12 is selected from hydrogen or a straight or branched alkyl group of from 1 to 4 carbon atoms and each of R 13 and R 14 is selected from hydrogen or a straight or branched alkyl group of from 1 to 4 carbon atoms.
  • Illustrative examples of the straight or branched alkyl groups of from 1 to 4 carbon atoms which R 3 and R 7 to R 14 , inclusive, may represent are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.
  • Illustrative examples of the straight or branched alkoxy groups of from 1 to 4 carbon atoms which R 8 may represent are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy and tert-butoxy.
  • the substituent group R 1 is hydrogen or methoxy.
  • R 2 is hydrogen, an alkanoyloxy group in which the alkanoyl moiety is straight or branched and has from 2 to 5 carbon atoms; or a heterocyclic thio group selected from 1,3,4-thiadiazol-2-ylthio, 5-methyl-1,3,4-thiadiazol-2-ylthio, 1,3,4-oxadiazol-2-ylthio, 5-methyl-1,3,4-oxadiazol-2-ylthio, tetrazol-5-ylthio, 1-methyltetrazol-5-ylthio, 1,2,3-triazol-5-ylthio, 1-methyl-1,2,3-triazol-5-ylthio and represented by the following respective structures: ##STR6##
  • alkanoyl groups represented by R 2 are the following: acetyl, propionyl and butyryl.
  • W is hydrogen or hydroxyl.
  • W is also --NHR 4 wherein R 4 is hydrogen, a straight or branched 2 to 5 carbon alkanoyl group or an alkoxycarbonyl group in which the alkoxy moiety is straight or branched and has from 1 to 4 carbon atoms.
  • W is a --COOR 5 or an --SO 3 R 5 group wherein R 5 is hydrogen or a straight or branched alkyl group of from 1 to 4 carbon atoms.
  • alkyl groups as represented by R 5 are: methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl.
  • Illustrative examples of the alkoxy groups of the alkoxycarbonyl groups represented by R 4 are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.
  • alkanoyl groups as represented by R 4 are acetyl, propionyl and isobutyryl.
  • R 1 exhibits either a cis or a trans spatial relationship with the hydrogen at position 6 in formula 1.
  • the cis and trans isomers are within the scope of the invention; the compounds with the cis configuration being preferred.
  • optical isomers of the compounds represented by formula 1 are also within the scope of this invention.
  • non-toxic pharmaceutically acceptable acid addition salts of compounds of formula 1 such as mineral acids, for example, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfate, sulfonate and phosphate and organic acid addition salts, for example, maleate, acetate, citrate, oxalate, succinate, benzoate, tartrate, fumarate, malate, mandelate and ascorbate are also included within the scope of this invention.
  • nontoxic pharmaceutically acceptable salts of compounds of formula 1 wherein W represents --CO 2 R 5 or --SO 3 R 5 (R 5 H) and R 3 is hydrogen.
  • these salts are the acid derivatives of primary, secondary and tertiary amines such as cyclohexylamine, dibutylamine, trioctylamine, procaine and dibenzylamine and the alkali metal and alkaline earth metal such as sodium, potassium, magnesium and calcium.
  • the compounds of this invention may be administered in a manner similar to that of many well known cephalosporin compounds, for example, cephalexin, cephalothin or cephaloglycine. They may be administered orally, parenterally or topically to warm blooded animals, that is, birds and mammals, for example, cats, dogs, cows, sheep, horses and humans.
  • cephalosporin compounds for example, cephalexin, cephalothin or cephaloglycine. They may be administered orally, parenterally or topically to warm blooded animals, that is, birds and mammals, for example, cats, dogs, cows, sheep, horses and humans.
  • the compounds may be administered in the form of tablets, capsules, or pills or in the form of elixirs or suspensions.
  • parenteral administration may be used in the form of a sterile aqueous solution which may contain other solutes, for example, enough saline or glucose to make the solutions isotonic.
  • topical administration the compounds may be incorporated in cream
  • bacteria against which the compounds of this invention are active are Staphylococcus aureus, Streptococcus pyogens, Escherichia coli and Klebsiella pneumonia.
  • An illustrative example of a compound of this invention is 7-[[amino(2,3-dihydro-5-benzofuranyl)acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
  • N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline may be used as a coupling agent in this reaction provided that when W is an --NHR 4 , an --OH, a --CO 2 R 5 or an --SO 3 R 5 group, R 4 and R 5 being hydrogen, in compounds represented by formula 3, then these groups must be protected; and further, in compounds represented by formula 2; R 3 must be other than hydrogen.
  • a dehydrating agent such as a carbodiimide may be used.
  • the protecting group(s) may be removed during work up of the reaction mixture by adjusting the pH to 1.5 to 3 or wherein R 3 , R 4 and/or R 5 are other than hydrogen by treating compounds of formula 1 with a 2 to 20 mole excess of an acid, e.g., trifluoroacetic acid at 0° to 30° C. for from 10 to 60 minutes.
  • an acid e.g., trifluoroacetic acid
  • protecting groups which are used for the specific reactive groups such as --NHR 4 , --OH, --CO 2 R 5 and --SO 3 R 5 wherein R 4 and R 5 are H are as follows.
  • the protecting group may be an acid salt such as the hydrochloride or the hydrobromide, an alkoxycarbonyl group, for example, tert-butoxycarbonyl; or an alkanoyl group, for example, an acetyl group or a [3-ethoxy-1-methyl-3-oxo-1-propen-1-yl] group.
  • the hydroxyl group may be protected with, for example, a trimethylsilyl group.
  • Acid groups such as --CO 2 H or --SO 3 H may be protected with an alkyl group such as methyl, ethyl, tert-butyl or with an alkanoyloxymethyl group such as pivaloyloxymethyl.
  • Compounds of formula 3 wherein W is a --NHR 4 , --OH, --CO 2 R 5 or an --SO 3 R 5 group wherein R 4 and R 5 are hydrogen and said groups are protected may be prepared by methods described in the literature or by methods described herein.
  • W is --NHR 4 (R 4 is hydrogen)
  • R 4 is hydrogen
  • the amine group in the amino acid of a compound of formula 3 may be protected by reaction with an alkoxycarbonylazide, in a solvent such as ethyl ether, chloroform, tetrahydrofuran, methylene chloride or benzene optionally in the presence of a base at from 0° C. to about 50° C. for from 1 hour to 24 hours.
  • the amine group of the amino acid of formula 3, W is --NHR 4 and R 4 is hydrogen, may be protected by reaction with the methyl, ethyl or propyl ester of acetoacetic acid.
  • the reaction is conducted in a low molecular weight alcohol, that is, methanol, ethanol, propanol containing sodium or potassium hydroxide at reflux temperature for from 5 to 30 minutes to form an amine protected with a [3-ethoxy-1-methyl-3-oxo-1-propen-1-yl] group.
  • a low molecular weight alcohol that is, methanol, ethanol, propanol containing sodium or potassium hydroxide at reflux temperature for from 5 to 30 minutes to form an amine protected with a [3-ethoxy-1-methyl-3-oxo-1-propen-1-yl] group.
  • W is --CO 2 R 5 and R 5 is hydrogen
  • R 5 is hydrogen
  • W is --CO 2 R 5 and R 5 is hydrogen
  • thionyl chloride in a solvent such as ethyl ether, methylene chloride or benzene at from 10° C. to the boiling point of the solution for from 0.5 hour to 6 hours.
  • the monoacid chloride is then reacted with a 1 to 4 carbon aliphatic alcohol optionally in the presence of an acid acceptor such as sodium bicarbonate or triethylamine at 10° to 80° C. for from 0.5 to 6 hours.
  • an acid acceptor such as sodium bicarbonate or triethylamine
  • W is --SO 3 R 5 and R 5 is hydrogen
  • R 5 is hydrogen
  • the chlorosulfonyl acetic acid derivative thus formed is reacted with a 1 to 4 carbon aliphatic alcohol in an excess of the alcohol at from 10° to 80° C. optionally in the presence of an acid acceptor for from 0.5 to 6 hours to give the desired compound of formula 3 wherein W is --SO 3 R.sub. 5 and R 5 is a 1 to 4 carbon alkyl group.
  • Functional equivalents of the acid as represented by compounds of formula 3 include the acid halide such as the acid chloride, acid anhydrides, including mixed anhydrides, with for example, alkylphosphoric acids, lower aliphatic monoesters of carbonic acid or alkyl or aryl sulfonic acids.
  • the coupling reaction is generally carried out in the presence of a solvent.
  • Suitable solvents include ethyl acetate, chloroform, acetone, dioxane, tetrahydrofuran (THF), dimethylformamide (DMF), ether, ethanol, benzene and ethanol-benzene.
  • hydrophilic solvents are employed, mixtures of these solvents with water are also suitable for the above reactions.
  • the coupling reaction is generally carried out in the presence of a base, for example, triethylamine or an alkaline bicarbonate.
  • the temperature of the reaction may vary from -10° C. to 100° C., and the reaction time may vary from about 0.5 hour to 24 hours.
  • the cephalosporin products are isolated by conventional means.
  • the acids as represented by compounds of formula 3 may be coupled as the (D), the (L) or mixtures of the (D) and (L) optical isomers when W is other than hydrogen or --CO 2 R 5 .
  • W is hydrogen or --CO 2 R 5 , no optical activity is present and these compounds are coupled as described above.
  • the acid to be coupled is reacted with a slight excess (1.05 equivalents) of an alkylchloroformate such as isobutylchloroformate at about -10° C. in a solvent which contains an acid acceptor such as triethylamine or sodium bicarbonate.
  • 1 equivalent of a compound represented by formula 2 is added, the temperature is raised from -10° C. to about 20° C. and the reaction completed after 2-3 hours.
  • the coupled product is recovered by known means.
  • a carbodiimide for example, N,N'-dicyclohexylcarbodiimide
  • Equivalent amounts of an acid, as represented by formula 3, and an amine, as represented by formula 2, and EEDQ in a suitable solvent such as benzene, chloroform, ethanol or THF at a temperature of from 10° C. to about 80° C. are reacted for about 1 to 24 hours. The solvent is removed and the coupled product is recovered by conventional methods.
  • an acid as represented by a compound of formula 3 may be converted to an acid chloride by means well-known in the art.
  • the acid chloride is reacted with an amine as represented by formula 2 in a suitable solvent which generally contains an acid acceptor such as triethylamine or an alkaline bicarbonate at a temperature of from 10° to 100° C. for from 0.5 hour to 4 hours.
  • the cephalosporin derivative is recovered by conventional means.
  • R 3 is alkanoyloxymethyl
  • R 3 is hydrogen, in the form of a salt, such as, an alkali metal salt (sodium) or the triethylammonium salt with an equivalent of a compound of the formula: ##STR9## wherein halo is chlorine or bromine, and R 5 is a straight or branched alkyl group of from 1 to 4 carbon atoms, by the general procedure described in U.S. Pat. No. 3,655,658.
  • ⁇ -hydroxyhippuric acid and 2,3-dihydrobenzofuran in a suitable solvent such as 5% to 50% sulfuric acid-95% to 50% acetic acid mixture, or from 50% to 100% sulfuric acid are reacted at from 0° to about 25° C. for from 1 hour to 72 hours.
  • a suitable solvent such as 5% to 50% sulfuric acid-95% to 50% acetic acid mixture, or from 50% to 100% sulfuric acid are reacted at from 0° to about 25° C. for from 1 hour to 72 hours.
  • ⁇ -Benzamido-(2,3-dihydro-5-benzofuranyl)acetic acid is recovered from the reaction mixture.
  • ⁇ -Amino(2,3-dihydro-5-benzofuranyl)acetic acid may be recovered from the corresponding ⁇ -benzamido derivative which is dissolved in a low molecular weight alcohol such as methanol, ethanol, isopropanol, butanol or water and subjected to hydrogen gas at a pressure of from 10 to 70 pounds/in 2 in the presence of a suitable catalyst such as palladium on carbon or palladium on barium sulfate for from 1 to 8 hours at a temperature of from 20° to 50° C.
  • a low molecular weight alcohol such as methanol, ethanol, isopropanol, butanol or water
  • hydrogen gas at a pressure of from 10 to 70 pounds/in 2
  • a suitable catalyst such as palladium on carbon or palladium on barium sulfate for from 1 to 8 hours at a temperature of from 20° to 50° C.
  • ⁇ -benzamido derivative dissolved in a low molecular weight alcohol such as methanol, ethanol, isopropanol or butanol or water containing a suitable mineral acid such as sulfuric, hydrochloric, hydrobromic or phosphoric acid for from 1 to 8 hours at a temperature of from about 30° to 110° C. and treating the thus formed acid salt with a base such as triethylamine, sodium hydroxide, potassium bicarbonate, sodium bicarbonate or a basic ion exchange resin such as Amberlite IR45® to form ⁇ -amino(2,3-dihydro-5-benzofuranyl)acetic acid.
  • a base such as triethylamine, sodium hydroxide, potassium bicarbonate, sodium bicarbonate or a basic ion exchange resin such as Amberlite IR45® to form ⁇ -amino(2,3-dihydro-5-benzofuranyl)acetic acid.
  • Compounds of formula 3 wherein W is --NHR 4 and R 4 is a 2 to 5 carbon alkanoyl group or an alkoxycarbonyl group wherein the alkoxy group contains 1 to 4 carbon atoms may be prepared by the following procedures.
  • An amine compound represented by formula 3 wherein W is --NHR 4 and R 4 is hydrogen is reacted in a suitable solvent such as ethyl ether, tetrahydrofuran, methylene chloride, chloroform or benzene with a 2 to 5 carbon acid halide, wherein the halide is chlorine or bromine, for example, acetyl chloride, propionyl chloride or butyryl bromide at 0° to 50° C. for from 1 to 24 hours optionally in the presence of a basic material such as triethylamine, sodium bicarbonate or sodium carbonate to give a compound of formula 3 wherein R 4 is a 2 to 5 carbon alkanoyl group.
  • a suitable solvent such as eth
  • An amine compound represented by formula 3 wherein W is --NHR 4 and R 4 is hydrogen may be reacted with an alkoxycarbonylazide wherein the alkoxy group is from 1 to 4 carbon atoms, for example, ethoxycarbonylazide, propoxycarbonylazide or isobutoxycarbonylazide in a suitable solvent such as ethyl ether, tetrahydrofuran, methylene chloride, chloroform or benzene optionally in the presence of basic material such as triethylamine, sodium bicarbonate or sodium carbonate at a temperature of from 0° to 50° C. for from 1 to 24 hours to produce a compound of formula 3 wherein W is --NHR 4 and R 4 is a 1 to 4 carbon alkoxycarbonyl group.
  • a suitable solvent such as ethyl ether, tetrahydrofuran, methylene chloride, chloroform or benzene
  • basic material such as triethylamine, sodium bi
  • the compound of formula 3 wherein W is a hydroxyl group may be prepared from the corresponding amine compound of formula 3, W is --NHR 4 and R 4 is hydrogen.
  • a suitable acid such as hydrochloric, hydrobromic, sulfuric, phosphoric or acetic acid
  • an alkali metal nitrite such as sodium nitrite or potassium nitrite at a temperature of from 30° to 70° C. for from 2 to 8 hours to give the desired ⁇ -hydroxy(2,3-dihydro-5-benzofuranyl)acetic acid.
  • the compound of formula 3 wherein W is hydrogen is prepared from the thus produced ⁇ -hydroxyacetic acid derivative.
  • the compound of formula 3 wherein W is hydroxyl is added to a low molecular weight alcohol such as methanol, ethanol, propanol or butanol which contains a suitable acid catalyst such as sulfuric, phosphoric, hydrochloric, or hydrobromic and is refluxed for from 1 to 6 hours and the ⁇ -hydroxy ester corresponding to the low molecular weight alcohol used is then recovered.
  • a low molecular weight alcohol such as methanol, ethanol, propanol or butanol which contains a suitable acid catalyst such as sulfuric, phosphoric, hydrochloric, or hydrobromic
  • the thus formed ⁇ -hydroxy ester may be reacted with either an acid anhydride such as acetic anhydride, propionic anhydride and butanoic anhydride or an alkanoyl halide such as acetyl chloride, propionyl bromide or butyryl chloride in a suitable solvent such as ethyl ether, tetrahydrofuran, methylene chloride or n-propyl ether at a temperature of from 10° C. to the reflux temperature of the solvent used for from 1 to 6 hours.
  • an acid anhydride such as acetic anhydride, propionic anhydride and butanoic anhydride
  • an alkanoyl halide such as acetyl chloride, propionyl bromide or butyryl chloride
  • a suitable solvent such as ethyl ether, tetrahydrofuran, methylene chloride or n-propyl ether
  • the alkanoyloxy ester derivative recovered is added to a low molecular weight alcohol such as methanol, ethanol, propanol or butanol and is treated with hydrogen gas at a pressure of 20 to 60 pounds/in 2 at 10° to 30° C. for from 1 to 4 hours in the presence of a suitable catalyst such as palladium on carbon or palladium on barium sulfate.
  • a suitable catalyst such as palladium on carbon or palladium on barium sulfate.
  • Basic hydrolysis of the ester with sodium hydroxide or potassium hydroxide followed by acid treatment gives a compound of formula 3 wherein W is hydrogen.
  • a compound represented by formula 3 wherein W is --CO 2 R 5 and R 5 is hydrogen or a 1 to 4 carbon alkyl group may be prepared by reacting a corresponding compound wherein W is hydrogen with 2 to 3 equivalents of lithium diisopropylamide or lithium diisopropylamine in a suitable solvent such as ethyl ether, propyl ether or tetrahydrofuran at -50° to 50° C. for from 1 to 2 hours.
  • the dianion thus formed is reacted with a suitable carboxylating agent such as methyl chloroformate, ethyl chloroformate, propyl chloroformate, butyl chloroformate, dimethylcarbonate or diethylcarbonate at -70° to -50° C. for from 10 to 60 minutes and recovering the monoester of a substituted malonic acid and hydrolyzing the ester with a suitable base such as sodium hydroxide or potassium hydroxide, followed by treatment with a suitable acid such as hydrochloric, sulfuric or phosphoric to give the substituted malonic acid.
  • a suitable carboxylating agent such as methyl chloroformate, ethyl chloroformate, propyl chloroformate, butyl chloroformate, dimethylcarbonate or diethylcarbonate at -70° to -50° C. for from 10 to 60 minutes
  • a suitable base such as sodium hydroxide or potassium hydroxide
  • a suitable acid such as hydrochloric,
  • a compound represented by formula 3 wherein W is --SO 3 R 5 and R 5 is hydrogen or a 1 to 4 carbon alkyl group may be prepared by reacting the corresponding compound wherein W is hydrogen with 1 to 2 equivalents of the dioxane-sulfur trioxide reagent in a suitable solvent such as methylene chloride, chloroform, carbon tetrachloride, ethylene dichloride or tetrachloroethane at a temperature of 0° to 30° C. for from 10 to 18 hours wherein the ⁇ -sulfo-(2,3-dihydro-5-benzofuranyl)acetic acid is obtained.
  • a suitable solvent such as methylene chloride, chloroform, carbon tetrachloride, ethylene dichloride or tetrachloroethane
  • the thus obtained acid is treated with 2 to 3 equivalents of a suitable reagent such as, for example, the bromide or chloride, of phosphorus pentahalide, phosphorus trihalide, phosphorus oxyhalide or thionyl halide in a suitable solvent such as ethyl ether, methylene chloride, chloroform or carbon tetrachloride or benzene at from 20° C. to the boiling point of the solution for from 0.5 to 6 hours to form the diacid halide; reacting the thus formed diacid chloride with 1 equivalent of water at 10° to 30° C.
  • a suitable reagent such as, for example, the bromide or chloride, of phosphorus pentahalide, phosphorus trihalide, phosphorus oxyhalide or thionyl halide in a suitable solvent such as ethyl ether, methylene chloride, chloroform or carbon tetrachloride or benzene
  • a suitable solvent such as ethyl ether, methylene chloride, chloroform, carbon tetrachloride or benzene and reacting the thus formed chlorosulfonyl acetic acid derivative with a 1 to 4 carbon alcohol such as methanol, ethanol, propanol or butanol optionally in the presence of a solvent such as ethyl ether or methylene chloride and optionally in the presence of an acid acceptor such as triethylamine, sodium bicarbonate or potassium carbonate at 70° to 80° C. for from 0.5 hour to 6 hours to form the ester corresponding to the alcohol employed of the ⁇ -(alkoxysulfony)(2,3-dihydro-5-benzofuranyl)acetic acid.
  • a suitable solvent such as ethyl ether, methylene chloride, chloroform, carbon tetrachloride or benzene and reacting the thus formed chlorosulfonyl acetic acid derivative
  • the compounds of formula 3 wherein W is as defined in formula 1 and the optical isomers of compounds of formula 3 wherein W is --NHR 4 , --OH, --SO 3 R 5 wherein R 4 and R 5 are as defined in formula 1 are deemed part of this invention.
  • the compounds of formula 3 defined above are useful in the synthesis of the cephalosporin derivatives of this invention.
  • the cephalosporin derivatives are active as antibacterial agents.
  • the resolving agent used to separate the optically active isomers of ⁇ -amino(2,3-dihydro-5-benzofuranyl)acetic acid is binaphthylphosphoric acid (BPA), formula 4, the structure of which is shown below. ##STR11## This material is fully described in Tetrahedron Letters, (1971), 4617.
  • the acid used in this invention is (+)-BPA.
  • the preferred compounds of this invention are compounds of formula 1 wherein W is hydrogen, amino, hydroxyl, carboxyl and sulfo; R 1 is hydrogen; R 2 is hydrogen, acetyloxy or heterocyclic thio and R 3 is hydrogen and the optical isomers thereof wherein the asymetric carbon atom of the 7- ⁇ -aminoacetamido group is in the (D) configuration.
  • the most preferred compound of this invention is the compound of formula 1 wherein R 1 , R 2 and R 3 are hydrogen and W is amino and the ⁇ -asymetric carbon atom of the 7-acetamido group is in the D-configuration.
  • the daily dosage of the active ingredient may range from 1 mg to about 500 mg. The exact amount will vary with the patient's size, age and type of infection.
  • a typical tablet can have the following composition:
  • cephalosporin derivative, lactose and cornstarch are mixed and ground through a number 12 screen.
  • the ground material is mixed with additional cornstarch as 10% starch paste and calcium stearate.
  • Suitable size tablets can be prepared using a 5/16 inch diameter standard concave punch.
  • a typical parenteral solution may have the following composition:
  • a typical ointment can have the following composition:
  • 2,3-Dihydrobenzofuran (4.8 g, 40 mmole) is stirred with 9.0 g (40 mmole) of ⁇ -hydroxy-hippuric acid in 200 ml of 10% H 2 SO 4 -90% acetic acid mixture.
  • the reaction is run at room temperature for 0.5 hour. After the half-hour, the reaction mixture is poured into 500 ml of water. The aqueous solution is extracted with ethyl acetate (4 ⁇ 100 ml). The ethyl acetate extracts are dried over magnesium sulfate and then evaporated to give ⁇ -benzamido(2,3-dihydro-5-benzofuranyl)acetic acid. Recrystallization of the crude benzamido compound from hexanemethylene chloride gives 11.56 g (94% yield).
  • ⁇ -Amino(2,3-dihydro-5-benzofuranyl)acetic acid (192 mg, 1 mmole) is added to 10 ml of 1:1 dioxane-water mixture with 4 mM of triethylamine and 0.17 ml of tert-butoxycarbonylazide. This mixture is stirred overnight at room temperature. The mixture is diluted with water and extracted with chloroform. The chloroform is dried and evaporated. The residue is taken up in ethyl acetate and washed with dilute aqueous hydrochloric acid. The organic layer is dried over magnesium sulfate and evaporated to give the title compound in a yield of about 80%.
  • ⁇ -Hydroxy(2,3-dihydro-5-benzofuranyl)acetic acid (10 mmole) is added to ethyl alcohol (20 ml) containing about 1 ml of concentrated sulfuric acid and the mixture heated for 2 hours. Approximately half of the alcohol is removed, the remainder of the mixture is poured into about 160 ml of water. The aqueous mixture is extracted with chloroform, the chloroform is dried and the solvents are removed. The residue is used without further purification.
  • ester prepared above (10 mmole) is added to about 25 ml of ether containing an acid acceptor such as triethylamine. Then acetyl chloride (10 mmole) is slowly added to the ether solution which begins to reflux from the liberated heat. After stirring for 0.5 hour the solvents are removed and ⁇ -acetyloxy(2,3-dihydro-5-benzofuranyl)acetic acid ethyl ester is recovered as the residue.
  • an acid acceptor such as triethylamine
  • the acetylated hydroxy ester (10 mmole) is dissolved in 40 ml of methanol to which is added about 50 mg of a palladium on carbon catalyst.
  • the mixture is subjected to 40 pounds/in 2 of hydrogen pressure for 4 hours. At the end of this time the mixture is filtered to remove the catalyst and the solvent is removed.
  • the residue, (2,3-dihydro-5-benzofuranyl)acetic acid, ethyl ester is dissolved in methanol and a 10% excess of sodium hydroxide is added.
  • the mixture is refluxed for about 60 minutes and the solvent removed by evaporation.
  • the residue is taken up in water and the pH adjusted to about 2 with hydrochloric acid.
  • the title compond precipiates from solution and is recovered by filtration.
  • the monoethyl ester of 2-(2,3-dihydro-5-benzofuranyl)-malonic acid (10 mmole) is added to methanol containing 11 mmole of sodium hydroxide. The mixture is refluxed for about 30 minutes and then the methanol is removed. The residue is taken up in water. Adjustment of the pH to 2 with hydrochloric acid results in the precipitation of the title acid. The title compound is filtered and dried.
  • the title compound is prepared by a modification of the procedure described in J. Am. Chem. Soc., 75, 1653 (1953). To a solution of ethylene chloride is added about 15 mmole of the dioxane-sulfur trioxide reagent and the temperature of the mixture warms to room temperature. (2,3-Dihydro-5-benzofuranyl)acetic acid (10 mmole) is added over a period of 30 minutes. The solution is stirred overnight at about 10° C. and then poured into cold water. The organic layer is separated and extracted with water. The aqueous extracts are combined with the water layer which is neutralized with sodium hydroxide and evaporated to dryness. The residue is extracted with 70% ethanol.
  • binaphthyl phosphoric acid (BPA)
  • BPA binaphthyl phosphoric acid
  • a racemic mixture of (D,L)- ⁇ -amino(2,3-dihydro-5-benzofuranyl)acetic acid is prepared according to the procedure in Example 2.
  • the racemic mixture 2.7 g (13.99 mmole)
  • BPA (+)-binaphthyl phosphoric acid
  • hydrochloric acid 25 ml of methanol.
  • This mixture is refluxed for 30 minutes.
  • the salt formed between (+)-BPA and D- ⁇ -amino(2,3-dihydro-5-benzofuranyl)acetic acid precipitates and is filtered. A total of 2.76 g (51%) of salt is obtained.
  • the reaction mixture is diluted with chloroform, washed with dilute aqueous hydrochloric acid, dilute aqueous sodium bicarbonate and water.
  • the chloroform solution is dried over magnesium sulfate, filtered and evaporated to dryness to give 3.3 g of solid.
  • This material is subjected to high pressure chromotography using 20% hexane in chloroform. About 2.4 g of the title compound is obtained.
  • NMR(DMSO-D 6 ) ppm( ⁇ )7.05(m,4); 5.85(q,2); 5.3(d,1); 5.01(d,1); 4.67(t,2); 3.32(m,4); 2.18(s,3); 1.70(s,9) and 1.60(s,9 ).
  • the white precipitate is the TFA salt of 7-[[amino(2,3-dihydro-5-benzofuranyl)acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid.
  • the aqueous phase is covered with a fresh layer of ethyl acetate, cooled in an ice bath and acidified to a pH of 3 with 6N hydrochloric acid. The mixture is filtered and the ethyl acetate separated. The aqueous phase is washed with fresh ethyl acetate. The combined ethyl acetate fractions are dried over magnesium sulfate, treated with charcoal, filtered and concentrated. The concentrate is then added with vigorous stirring to a mixture of ether-hexane.
  • the mixture is stirred for 18 hours at 20° C.
  • the mixture is filtered to remove solids and the THF is then removed under reduced pressure.
  • the residue is taken up in ethyl acetate which is extracted with aqueous sodium bicarbonate and then with water.
  • the ethyl acetate solution is dried over magnesium sulfate and then evaporated to give the title compound.
  • the protecting groups may be removed using the procedure of Example 10.
  • ⁇ -Sulfo(2,3-dihydro-5-benzofuranyl)acetyl chloride is prepared according to the general method described in J. Med. Chem., 15, 1105 (1972). ⁇ -Sulfo(2,3-dihydro-5-benzofuranyl)acetic acid 20 mmole is added slowly to a solution of diethyl ether (4 ml) and thionyl cloride (150 mmole). The mixture is stirred at room temperature until the gas evolution stops. Then about 0.2 ml of dimethylformamide is added and the solution heated at 40° C. for 4 hours.
  • the mixture is diluted with 30 ml of diethyl ether and 30 ml of hexane and then cooled to about -25° C.
  • the ⁇ -sulfo(2,3-dihydro-5-benzofuranyl)acetyl chloride is recovered from the mixture and used without further purification.
  • the aqueous phase is layered with ethyl acetate and the pH of the aqueous solution is adjusted to 1.5.
  • the ethyl acetate is then separated from the aqueous phase, dried over magnesium sulfate, filtered and evaporated to give the title compound.
  • a solution of 10 mmole of 2,3-dihydo-5-benzofuranyl acetic acid and 10 mmole of triethylamine in 100 ml of THF is cooled to about 0° C. While stirring, isobutylchloroformate (10 mmole) is added and the temperature maintained at 0° C. for 15 minutes.
  • a cold solution of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (10 mmole) and 10 mmole of triethylamine in 80 ml of 50% aqueous THF is added to the previously prepared solution.
  • the mixture is stirred at 5° C. for 1 hour and at room temperature for 1 hour. Then the THF is evaporated and the residue is dissolved in water and washed with ethyl acetate.
  • the aqueous phase is covered with ethyl acetate and the pH is adjusted to 3 with 6N hydrochloric acid.
  • the mixture is filtered and the layers separated.
  • the ethyl acetate is dried over magnesium sulfate, filtered and evaporated to give the title compound.
  • ⁇ -Sulfo(2,3-dihydro-5-benzofuranyl)acetic acid as prepared in Example 7, (5 mmole) is added to 50 ml of ether and 55 mmole of thionyl chloride and 0.3 ml of dimethylformamide. This mixture is stirred at 20° C. for 50 hours. At the end of this time the ether and the excess thionyl chloride are removed. The dichloride crystalizes after it is cooled overnight. Then 5 mmole of the dichloride is added to 50 ml of anhydrous ether. Then 10 ml of ether containing 5 mmole of water is added and the mixture stirred. The hydrolysis is being complete, The solvent is removed along with the hydrogen chloride liberated. The residue is ⁇ -chlorosulfonyl(2,3-dihydro-5-benzofuranyl)acetic acid.
  • ⁇ -Chlorosulfonyl(2,3-dihydro-5-benzofuranyl)acetic acid (5 mmole) is added to 30 ml of ethyl ether. To this mixture is added 5 mmole of ethanol in 10 ml of ethyl ether which contains 10 mmole of triethylamine. The mixture is stirred at 20° C. for about 1 hour and 50 ml of water is added. The pH is adjusted to about 6.5 and the layers separated. The organic layer is dried over magnesium sulfate, filtered and evaporated to give ⁇ -ethoxysulfonyl(2,3-dihydro-5-benzofuranyl)acetic acid.
  • This ether solution is added to 10 ml of water containing 5 mmole of 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 10 mmole of sodium bicarbonate.
  • the temperature of the aqueous solution is about 10° C.
  • the pH is adjusted to about 2.
  • Ethyl acetate is added, the mixture is thoroughly agitated and the layers separated. The organic layer is dried over magnesium sulfate, filtered and evaporated to give the title compound.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cephalosporin Compounds (AREA)
US05/881,611 1978-02-27 1978-02-27 7-(2,3-Dihydrobenzo-5-furanyl)-acetamido cephalosporin derivatives Expired - Lifetime US4229575A (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
US05/881,611 US4229575A (en) 1978-02-27 1978-02-27 7-(2,3-Dihydrobenzo-5-furanyl)-acetamido cephalosporin derivatives
ZA79254A ZA79254B (en) 1978-02-27 1979-01-22 7-(2,3-dihydrobenzo-5-furanyl)acetamido cephalosporin derivatives
AU43701/79A AU516917B2 (en) 1978-02-27 1979-01-26 7-(2,3-dihydrobenzo-5-furanyl)acetamido cephalosporin derivatives
IE790141A IE790141L (en) 1978-02-27 1979-01-30 Cephalosporins and benzofuranylacetic acids.
DE19792903909 DE2903909A1 (de) 1978-02-27 1979-02-02 7-(2,3-dihydrobenzo-5-furanyl)- acetamido-cephalosporinderivate und verfahren zu deren herstellung
IL56574A IL56574A0 (en) 1978-02-27 1979-02-02 7-(2,3dihydrobenzo-5-furanyl)acetamido ciphalosporin derivatives
FR7904285A FR2418234A1 (fr) 1978-02-27 1979-02-20 Derives d'acide 7-(2,3-dihydrobenzo-5-furannyl)acetamidocephalosporanique utiles notamment comme antibiotiques et leur procede de preparation
GB7906143A GB2014996B (en) 1978-02-27 1979-02-21 Arylacetamidocephalosporins
NL7901484A NL7901484A (nl) 1978-02-27 1979-02-26 Nieuwe cefalosporinederivaten, de bereiding daarvan en de toepassing daarvan als antibiotica.
BE193693A BE874450A (fr) 1978-02-27 1979-02-26 Derives d'acide 7-(2,3-dihydrobenzo-5-furannyl) acetamidocephalosporanique utiles notamment comme antibiotiques et leur procede de preparation
JP2090079A JPS54122290A (en) 1978-02-27 1979-02-26 77*2*33dihydrobenzoo55furanyl*acetoamide cephalosporin derivatives
FR7918366A FR2428636A1 (fr) 1978-02-27 1979-07-16 Nouveaux acides dihydrobenzofurannylacetiques a-substitues, et leur preparation

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US05/881,611 US4229575A (en) 1978-02-27 1978-02-27 7-(2,3-Dihydrobenzo-5-furanyl)-acetamido cephalosporin derivatives

Publications (1)

Publication Number Publication Date
US4229575A true US4229575A (en) 1980-10-21

Family

ID=25378826

Family Applications (1)

Application Number Title Priority Date Filing Date
US05/881,611 Expired - Lifetime US4229575A (en) 1978-02-27 1978-02-27 7-(2,3-Dihydrobenzo-5-furanyl)-acetamido cephalosporin derivatives

Country Status (11)

Country Link
US (1) US4229575A (fr)
JP (1) JPS54122290A (fr)
AU (1) AU516917B2 (fr)
BE (1) BE874450A (fr)
DE (1) DE2903909A1 (fr)
FR (2) FR2418234A1 (fr)
GB (1) GB2014996B (fr)
IE (1) IE790141L (fr)
IL (1) IL56574A0 (fr)
NL (1) NL7901484A (fr)
ZA (1) ZA79254B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4501741A (en) * 1983-04-12 1985-02-26 Eli Lilly And Company Cephalosporin antibiotics

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816473A (en) * 1983-07-14 1989-03-28 Syntex (U.S.A.) Inc. Aroyl benzofuran and benzothiophene acetic and propionic acids
DE3508258A1 (de) * 1985-03-08 1986-09-18 Bayer Ag, 5090 Leverkusen Ss-lactamantibiotika, verfahren zur herstellung und ihre verwendung als und in arzneimitteln
DE3509618A1 (de) * 1985-03-16 1986-09-18 Bayer Ag, 5090 Leverkusen Ss-lactam-antibiotika, verfahren zur herstellung und ihre verwendung als arzneimittel
DE3733626A1 (de) * 1987-10-05 1989-04-13 Bayer Ag Heteroanellierte phenylglycin-(beta)-lactam-antibiotika, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3989694A (en) * 1974-12-27 1976-11-02 Smithkline Corporation 7-Acyl-3-(substituted triazolyl thiomethyl)cephalosporins
US4000133A (en) * 1973-06-06 1976-12-28 Fujisawa Pharmaceutical Co., Ltd. Substituted 7-styryl-carbonyloxy-acetamido cephalosporanic
US4020060A (en) * 1975-07-22 1977-04-26 Richardson-Merrell Inc. 7-[α-Amino-ω-(3,4-methylenedioxyphenyl)acylamido]cephalosporanic acid derivatives
US4033956A (en) * 1975-07-22 1977-07-05 Richardson-Merrell Inc. 7[α-Amino-ω-(2,3-methylenedioxy-phenyl)acylamido]cephalosporanic acid derivatives

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1109527A (en) * 1965-02-19 1968-04-10 Erba Carlo Spa New substituted acetic acids
FR2077733B1 (fr) * 1970-02-10 1973-03-16 Roussel Uclaf
GB1483061A (en) * 1974-06-12 1977-08-17 Schiapparelli Stabilment Benzopyranyl-,naphtho-(2,1-6)furanyl-,and naphtho(2,1-6)pyranyl-substituted acetic and propionic acid derivatives
US4138397A (en) * 1978-02-27 1979-02-06 Richardson-Merrell Inc. 6-(2,3-Dihydro-5-benzofuranyl)acetamido penicillin derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4000133A (en) * 1973-06-06 1976-12-28 Fujisawa Pharmaceutical Co., Ltd. Substituted 7-styryl-carbonyloxy-acetamido cephalosporanic
US3989694A (en) * 1974-12-27 1976-11-02 Smithkline Corporation 7-Acyl-3-(substituted triazolyl thiomethyl)cephalosporins
US4020060A (en) * 1975-07-22 1977-04-26 Richardson-Merrell Inc. 7-[α-Amino-ω-(3,4-methylenedioxyphenyl)acylamido]cephalosporanic acid derivatives
US4033956A (en) * 1975-07-22 1977-07-05 Richardson-Merrell Inc. 7[α-Amino-ω-(2,3-methylenedioxy-phenyl)acylamido]cephalosporanic acid derivatives

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4501741A (en) * 1983-04-12 1985-02-26 Eli Lilly And Company Cephalosporin antibiotics

Also Published As

Publication number Publication date
GB2014996B (en) 1982-09-29
IE790141L (en) 1979-08-27
GB2014996A (en) 1979-09-05
JPS54122290A (en) 1979-09-21
IL56574A0 (en) 1979-05-31
NL7901484A (nl) 1979-08-29
FR2428636A1 (fr) 1980-01-11
AU516917B2 (en) 1981-06-25
AU4370179A (en) 1979-09-06
BE874450A (fr) 1979-06-18
DE2903909A1 (de) 1979-08-30
FR2418234A1 (fr) 1979-09-21
ZA79254B (en) 1980-01-30

Similar Documents

Publication Publication Date Title
US4138397A (en) 6-(2,3-Dihydro-5-benzofuranyl)acetamido penicillin derivatives
US4007177A (en) Cephalosporin derivatives
US4045438A (en) Cephalosporin antibiotics
JPS6150957B2 (fr)
US4918068A (en) Cephem compounds
US4260607A (en) Cephalosporin esters
JPS6156239B2 (fr)
US4229575A (en) 7-(2,3-Dihydrobenzo-5-furanyl)-acetamido cephalosporin derivatives
US4093802A (en) Thiocarbamatemethyl-substituted cephalosporin derivatives
US3919208A (en) 7-(Cyanomethylaryl)acetamide-cephalosporin derivatives
US4148997A (en) 7-[Sulfomethyl)phenyl]acetamidocephalosporin derivatives
US4183925A (en) 7-Aminophenylacetamido-Δ3 -cephem antibacterial agents and method of use
US4219648A (en) 7-[[Amino(1,3-dihydrobenzo[c]thienyl)acetyl]amino]cephalosporin derivatives
US4180660A (en) Cephalosporin derivatives
US4150224A (en) 7[[(1-Pyrrollyl)7 acetyl]amino]cephalosporin derivatives
US4122260A (en) Cephalosporin derivatives
US4200747A (en) 7-2-Indolyl acetamido cephalosporin derivatives
US4148998A (en) Pyrrole cephalosporin derivatives
US4093804A (en) Pyridiniummethylaryl-substituted cephalosporin derivatives
US4139703A (en) Indole cephalosporin derivatives
US4229574A (en) Indole cephalosporin derivatives
US4172941A (en) 7-[2-[ω-(1,3-Dithiolan-2-imino)substituted]-acetylamino]cephalosporanic acid derivatives
JPS6133825B2 (fr)
USRE29164E (en) 7-Amino-cephalosporanic and decephalosporanic acid derivatives
US4137314A (en) 7-Dithioacetamido cephalosporins and pharmaceutical compositions and methods employing them having antibacterial activity